Electrocardiogram signal variance analysis in the diagnosis of coronary artery disease—A comparison with exercise stress test in an angiographically documented high prevalence population

Variance electrocardiography (variance ECG) is a new resting procedure for detection of coronary artery disease (CAD). The method measures variability in the electrical expression of the depolarization phase induced by this disease. The time-domain analysis is performed on 220 cardiac cycles using high-fidelity ECG signals from 24 leads, and the phase-locked temporal electrical heterogeneity is expressed as a nondimensional CAD index (CAD-I) with the values of 0–150. This study compares the diagnostic efficiency of variance ECG and exercise stress test in a high prevalence population. A total of 199 symptomatic patients evaluated with coronary angiography was subjected to variance ECG and exercise test on a bicycle ergometer as a continuous ramp. The discriminant accuracy of the two methods was assessed employing the receiver operating characteristic curves constructed by successive consideration of several CAD-I cutpoint values and various threshold criteria based on ST-segment depression exclusively or in combination with exertional chest pain. Of these patients, 175 with CAD (≥ 50% luminal stenosis in 1 + major epicardial arteries) presented a mean CAD-I of 88 ± 22, compared with 70 ± 21 in 24 nonaffected patients (p < 0.01). Variance ECG provided a stochastically significant discrimination (p < 0.01) which was matched by exercise test only when chest pain variable was added to ST-segment depression as a discriminating criterion. Even then, the exercise test diagnosed single-vessel disease with a significantly lower sensitivity. At a cutpoint of CAD-I ≥ 70, compared with ST-segment depression ≥ 1 mm combined with exertional chest pain, the overall sensitivity of variance ECG was significantly higher (p < 0.01) than that of exercise test (79 vs. 48 %). When combined, the two methods identified 93% of coronary angiography positive cases. Variance ECG is an efficient diagnostic method which compares favorably with exercise test for detection of CAD in high prevalence population.     

Total ankle replacement for posttraumatic arthritis: Similar outcome in postfracture and instability arthritis: a comparison of 90 ankles

Background and purpose

Most studies on total ankle replacement (TAR) have used a case mix of patients. We evaluated the outcome of TAR performed for end-stage arthritis either because of fracture or ligamentous injury.

Patients and methods

We prospectively followed 88 consecutive patients (50 postfracture ankles and 40 ankles with instability arthritis (2 bilateral)) who underwent TAR between 2001 and 2009. Mean follow-up for both groups was 5 years.

Results

Preoperative varus deformity of 10° or more was present in 23 ankles in the instability group. At 6 years, survival with revision or salvage fusion as an endpoint was 87% (95% CI: 74–99) in the postfracture group and 79% (95% CI: 63–94) in the instability group. Progressive periprosthetic osteolysis was seen in 23 ankles, and required salvage fusion in 6. The number of reoperations was similar in both groups. Clinical outcome, as assessed with 2 ankle scores and 2 questionnaires, showed good results and was similar at the latest follow-up.

Interpretation

The outcome was similar in the postfracture and instability groups and also similar to that reported in series including a case mix of patients. In contrast to earlier reports, preoperative frontal plane deformity in this series was not identified as a risk factor for failure.Most published articles on total ankle replacement (TAR) have presented results from mixed cohorts of patients suffering from end-stage ankle arthritis of several different etiologies, such as posttraumatic arthritis, primary arthritis, and rheumatoid arthritis (Buechel et al. 2003, Wood et al. 2008, Bonnin et al. 2011, Rippstein et al. 2011, Barg et al. 2013, Zaidi et al. 2013). To our knowledge, there have been no studies on TAR concentrating exclusively on patients withposttraumatic arthritis, but some studies have focused on TAR in combined cohorts of posttraumatic and primary osteoarthritis (Saltzman et al. 2010, Bai et al. 2010, Flavin et al. 2013).This is surprising, as posttraumatic arthritis is considered to be the most frequent cause of ankle arthritis (Saltzman et al. 2005).2 subgroups of posttraumatic arthritis should be distinguished: (1) postfracture arthritis, secondary to an intra- or juxta-articular fracture; and (2) ligamentous posttraumatic arthritis, secondary to a single severe ankle sprain or as a result of recurrent or chronic instability (Valderrabano et al. 2009). We refer to the latter as instability arthritis. Patients suffering from end-stage instability arthritis frequently present with a varus deformity of the ankle as a result of both lateral ligament laxity and asymmetric cartilage loss medially (Harrington 1979, Doets et al. 2008, Ryssman and Myerson 2011).We evaluated the medium-term outcome of TAR for end-stage posttraumatic ankle arthritis and compared it for postfracture arthritis and for instability arthritis. Our research questions were whether patients treated with TAR for instability arthritis—as they more frequently have a deformity and perhaps also residual instability after TAR—will have worse results with respect to (1) implant survival, (2) the number of reoperations, and (3) ankle-specific and general patient- and physician-based outcomes.     

Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination

Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59’s hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF)^βTrCP E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant Ub^R54A/Y59A diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by Ub^R54A/Y59A or Ub^K48R yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.Central to selective protein turnover by the 26S proteasome is the formation of homotypic lysine 48 (K48)-linked ubiquitin (Ub) chains that tag substrate proteins for degradation (1). Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein). As such, the organization of CRL subunits positions the substrate receptor (such as the F-box protein) within the proximity of ROC1, which recruits an E2-conjugating enzyme that catalyzes the transfer of Ub to a bound substrate. In the SCF reconstitution system, K48-linked polyubiquitin chains on a substrate such as IκBα and β-catenin are produced in a two-step reaction. The E2 UbcH5c deposits the first Ub moiety, forming a substrate–Ub linkage, which is followed by repeated discharge of subsequent Ubs by E2 Cdc34 to form K48-specific Ub chains (3). Human Cdc34 contains a highly conserved charged acidic loop (residues 102–113) that participates in the elongation of K48 chains (4, 5). The current work addresses whether there are determinants on the Ub itself that dictate K48 linkage specificity and, moreover, how Cdc34 might recognize Ub K48.     

Biogeography of time partitioning in mammals

Many animals regulate their activity over a 24-h sleep–wake cycle, concentrating their peak periods of activity to coincide with the hours of daylight, darkness, or twilight, or using different periods of light and darkness in more complex ways. These behavioral differences, which are in themselves functional traits, are associated with suites of physiological and morphological adaptations with implications for the ecological roles of species. The biogeography of diel time partitioning is, however, poorly understood. Here, we document basic biogeographic patterns of time partitioning by mammals and ecologically relevant large-scale patterns of natural variation in “illuminated activity time” constrained by temperature, and we determine how well the first of these are predicted by the second. Although the majority of mammals are nocturnal, the distributions of diurnal and crepuscular species richness are strongly associated with the availability of biologically useful daylight and twilight, respectively. Cathemerality is associated with relatively long hours of daylight and twilight in the northern Holarctic region, whereas the proportion of nocturnal species is highest in arid regions and lowest at extreme high altitudes. Although thermal constraints on activity have been identified as key to the distributions of organisms, constraints due to functional adaptation to the light environment are less well studied. Global patterns in diversity are constrained by the availability of the temporal niche; disruption of these constraints by the spread of artificial lighting and anthropogenic climate change, and the potential effects on time partitioning, are likely to be critical influences on species’ future distributions.Natural cycles of light and darkness structure the environment of the majority of eukaryotic organisms. The rotation of the Earth partitions time into regular cycles of day and night, and although all points on the Earth’s surface receive roughly equal durations of light and darkness over the course of a year, at mid to high latitudes seasonal variation in day length imposes an uneven distribution throughout the annual cycle. During the hours when the sun is below the horizon, there is seasonal and latitudinal variation in the duration of “biologically useful semidarkness” in the form of twilight and moonlight (1), modified by both the lunar cycle and variable cloud cover, providing changing opportunities for animals able to use visual cues for key behaviors including foraging, predator avoidance, and reproduction (2–6). Activity during both daylight and semidarkness may be further constrained by covariance between the natural cycles of light and temperature; the metabolic costs of thermoregulation place constraints on the time available for activity (7). Thermal constraints may limit nocturnal activity when nighttime temperatures are low, and diurnal activity when temperatures are high. Furthermore, energetic constraints may force some species to be active throughout hours of both light and darkness (8). Where energetic and thermal costs are not prohibitive, temporal niche partitioning may occur as species specialize and avoid competition by concentrating their activity within a particular section along the light gradient (9, 10). Behavioral traits are associated with a range of specialized adaptations, particularly in visual systems and eye morphology (11) and energetics and resource use (6, 12). Thus, some species are apparently obligately diurnal in their peak activity patterns, some obligately nocturnal, obligately crepuscular (active primarily during twilight), or obligately cathemeral (significant activity both during daylight and night), and others make facultative use of both daylight and night (13), or show seasonal and/or geographical variation in their strategy. Strict nocturnality and diurnality are hence two ends of a continuum of possible strategies for partitioning time over the 24-h cycle. As properties of organisms that strongly influence performance within a particular environment, these strategies can be considered functional traits in themselves (14), but are also associated with suites of adaptations, with implications for the ecological roles of species and individuals. Crepuscular and cathemeral species may have intermediate adaptations (15), and behavior may be flexible to vary within species and among individuals according to factors such as time of year, habitat structure, food availability, age, temperature, and the presence or absence of predators (16–18).The ecology of diel time partitioning by organisms remains rather poorly understood (19, 20). Studies have considered the adaptive mechanisms behind strategies within a single ecosystem, including predator avoidance, energetic constraints, diet quality, and interspecific competition (9, 21). Meanwhile, although mapping functional traits has become a core technique in functional biogeography (22, 23), surprisingly little is known about the biogeography of diel activity patterns, and the extent to which they are determined by geographic gradients in light and climate. Addressing such issues has become more pressing with growth in the evidence for a wide range of ecological impacts of both anthropogenic climatic change and nighttime light pollution (24–28). Natural cycles of light have remained consistent for extremely long geological periods, providing a rather invariant context, and a very reliable set of potential environmental cues. The continued spread of electric lighting has caused substantial disruption to how these cycles are experienced by many organisms, exerting a novel environmental pressure (29). Direct illumination of the environment has quite localized effects, but sky glow—the amplified night sky brightness that is produced by upwardly emitted and reflected electric light being scattered by water, dust, and gas molecules in the atmosphere—can alter light regimes over extensive areas. Indeed, under cloudy conditions in urban areas, sky glow has been shown to be of an equivalent or greater magnitude than high-elevation summer moonlight (30). Understanding the biogeography of time partitioning by organisms provides a first step toward determining where such changes are likely to have the greatest impact.In this paper, we (i) document basic biogeographic patterns of time partitioning by organisms, using terrestrial mammals as a case study; (ii) document ecologically relevant large-scale patterns of natural variation in “biologically useful” natural light, constrained by temperature; and (iii) determine how well the first of these are predicted by the second. Mammals provide an interesting study group, being globally distributed, occupying a broad range of environments, and exhibiting a wide diversity of time-partitioning behavior. Much concern has also been expressed as to the potential impacts of nighttime light pollution on the group, and there are many studies documenting significant influences (31, 32). Due to the global nature of this study, and the paucity of detailed information on time partitioning reported for many species, our focus is on a high-level categorization, allocating species to one of four temporal niches: nocturnal, diurnal, cathemeral, and crepuscular (Fig. 1), albeit with the acknowledgment that in many species behavior occurs along a continuum of possible strategies that may be more flexible and complex.Open in a separate windowFig. 1.Examples of recorded diel activity patterns illustrating the four main time-partitioning strategies used to classify terrestrial mammals in this study (64–67).     

Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium,cartilage, and bone in the LITHE study

Objective

We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker.

Methods

The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared.

Results

At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose.

Conclusions

TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist.